CN1045955C - New active compounds - Google Patents

New active compounds Download PDF

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Publication number
CN1045955C
CN1045955C CN94192410A CN94192410A CN1045955C CN 1045955 C CN1045955 C CN 1045955C CN 94192410 A CN94192410 A CN 94192410A CN 94192410 A CN94192410 A CN 94192410A CN 1045955 C CN1045955 C CN 1045955C
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compound
gram
quinoline
mmole
milliliters
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CN1125438A (en
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C·I·斯塔克
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AstraZeneca AB
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Astra AB
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Priority claimed from SE9303970A external-priority patent/SE9303970D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

The present invention relates to novel quinoline derivatives of formula (I) which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

Description

Quinoline and method for making thereof and purposes and the pharmaceutical composition that contains this derivative
Technical field
The present invention relates to a class new compound and aspect treatment acceptable salt, therefore they can suppress the gastric acid secretion of external source or endogenous stimulation, can be used for prevention and treatment gastrointestinal inflammation.Further, the The compounds of this invention that the present invention relates to be used for the treatment of, the preparation method who relates to this class new compound, relate to and contain at least a The compounds of this invention or its acceptable salt aspect treatment is the pharmaceutical composition of activeconstituents, and relate to the purposes of this active compound when making the medicine that can in above-mentioned medical applications, use.
Background technology
In prior art, such as from EP-A1-259, knowing in 174 and EP-A1-330,485 can gastric acid inhibitory excretory substituted chinoline derivative.
The present invention's narration
Be surprised to find that; as the quinoline that is replaced by alkylthio oxyethyl group, alkylthio, propoxy-, alkyl sulfenyl oxyethyl group, alkyl sulfenyl propoxy-, alkyl sulfonyl oxyethyl group or alkyl sulfonyl propoxy-at 8; formula I compound 4-amino-3-acyl group quinoline is effectively as gastric acid secretion inhibitor, and they are by suppressing stomach and intestine H +, K +-adenosine triphosphatase is brought into play this usefulness.
Therefore, in one aspect, the present invention relates to the compound of formula I or its at pharmaceutically acceptable salt:
Figure C9419241000091
R wherein 1Be (a) C 1～C 6Alkyl, (b) C 3～C 6Cycloalkyl, perhaps (c) C 3～C 6, C 1～C 6Cycloalkylalkyl; R 2Be (a) H, (b) C 1～C 5Alkyl, (c) C 1～C 5Alkoxyl group, perhaps (d) halogen; R 3Be C 1～C 5Alkyl; R 4Be (a) H (b) C 1～C 4Alkyl,
(c) halogen, perhaps
(d)OH；
M is integer 2 or 3; And
N is an integer 0,1 or 2.
In full piece of writing specification sheets and appended claim, given chemical formula or chemical name will comprise whole steric isomers and optical isomer, and their racemic modification, at this these isomer are arranged, and their medicine can be by acid salt that is subjected to and their solvate, such as hydrate.
In full piece of writing specification sheets and appended claim, all will adopt following definition.
Unless otherwise prescribed or the explanation, term " C 1～C 5Alkyl " representative has the straight or branched alkyl of 1～6 carbon atom.The example of described low alkyl group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl and straight chain and side chain amyl group and hexyl.
Unless otherwise prescribed or the explanation, on behalf of its ring, term " cycloalkyl " contain C 3～C 6Cycloalkyl, on ring, can contain the substituting group of low alkyl group arbitrarily.The example of described cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and suberyl.
Unless otherwise prescribed or the explanation, term " C 1～C 6Alkoxyl group " representative contains the alkoxyl group of straight or branched of 1～6 carbon atom.Described lower alkoxy comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy and straight chain and side chain pentyloxy and hexyloxy.
Unless otherwise prescribed or the explanation, term " halogen " will mean fluorine, chlorine, bromine or iodine.
Different according to processing condition with raw material, the final product that obtains the formula I with the form of neutral form or salt.Be that the free alkali or the salt of these final products are all within the scope of the invention.
The acid salt of this new compound can use alkaline reagents such as alkali or ion-exchange to be transformed into free alkali himself to be known method.This free alkali that obtains also can form salt with organic acid or mineral acid.
When the preparation acid salt, preferably use the acid that can form the suitable acceptable salt of therapeutics.The example of this class acid is haloid acid, sulfonic acid, phosphoric acid, nitric acid, aliphatics, alicyclic, aromatic series or heterocycle family carboxylic acid or sulfonic acid, as formic acid, acetate, propionic acid, succsinic acid, oxyacetic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, pyruvic acid, P-hydroxybenzoic acid, pamoic acid, methylsulfonic acid, ethyl sulfonic acid, ethylenehydrinsulfonic acid, halobenzene sulfonic acid, toluenesulphonic acids or naphthene sulfonic acid.
Preferred formula I compound is just like undefined compound: R 1Be CH 3, CH 2CH 3, CH 2CH 2CH 3, CH (CH 3) 2, cyclopropyl or ring
The propyl group methyl; R 2Be CH 3, CH 2CH 3, CH 2CH 2CH 3, CH (CH 3) 2,
CH (CH 3) CH 2CH 3, OCH 3, OCH 2CH 3Or halogen; R 3Be CH 3, CH 2CH 3, CH (CH 3) 2Or CH 2CH 2CH 3And R 4Be H, CH 3, CH 2CH 3, halogen or OH.
Preferred formula I compound wherein, R 1Be CH 2CH 3Or CH 2CH 2CH 3R 2Be CH 3, CH 2CH 3, CH (CH 3) 2, OCH 3Or Cl; R 3Be CH 3, CH 2CH 3Or CH 2CH 2CH 3And R 4Be H, CH 3, F, Cl or OH.
In most preferred The compounds of this invention, R 1Be CH 2CH 2CH 3R 2And R 3Be CH 3R 4Be H; M is 2; N is 1, i.e. 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methyl sulfinyl oxyethyl group) quinoline.
Again further, the compound of the formula I that the present invention relates in treatment, use.
Preparation
The present invention also provides the manufacture method of the compound with formula I.This compounds prepares by following method:
(A) compound of the compound of general formula II and general formula III reaction:
Figure C9419241000121
Here R 2And R 4As the front definition,
Figure C9419241000122
R in the formula 1, R 3, m and n such as front define, X is a leavings group, as halogen, tosyloxy or mesyloxy.
The compound of formula III is a novel cpd, shows as another aspect of the present invention.
Have solvent or solvent-free under carry out this reaction.When using solvent, preferred solvent is acetonitrile, tetrahydrofuran (THF), toluene or dimethyl formamide.
When reacting with solvent, temperature of reaction is generally from about 20 ℃ of boiling points to about solvent for use, more preferably from about 20 ℃ to about 110 ℃.Reaction times is generally from about 1 hour to about 24 hours.
When reacting without solvent, temperature of reaction is generally from about 30 ℃ to about 170 ℃.Reaction times is generally from 15 minutes to about 2 hours.
(B) pass through R in the formula 1, R 2, R 3, R 4With the formula I compound of definition and n=0 among m such as front (A) carry out oxidation can preparation formula in R 1, R 2, R 3, R 4And definition and n is 1 or 2 formula I compound among m such as front (A).
Use oxygenant such as clorox, nitric acid, hydrogen peroxide (in case of necessity in the presence of vanadium compound), peracid, cross ester class, ozone, nitrogen tetroxide, iodosobenzene, N-halo succinimide, 1-chlorobenzotriazole, t-butyl hypochlorite's ester, diazabicylo [2,2,2]-octane bromine title complex, sodium metaperiodate, tin anhydride, Manganse Dioxide, chromic acid, ceric ammonium nitrate, bromine, chlorine and SULPHURYL CHLORIDE can carry out this oxidizing reaction.This oxidation occurs in the solvent as halohydrocarbon, alcohols, ethers or ketone.
Oxidizing reaction also can carry out enzyme catalysis or ferment with suitable microorganism carrying out with enzyme.
The compound of general formula II is the commodity buyables, also can be by known method preparation.
The compound of general formula III can prepare with the following examples in accordance with known methods.
Use
Aspect another, the present invention relates to as the defined compound in front in the application aspect secretion of manufacturing gastric acid inhibitory or the treatment gastrointestinal inflammation medicine.
On meaning more generally, compound of the present invention can be used to prevent and treat and comprises human mammiferous gastrointestinal inflammation and the symptom relevant with hydrochloric acid in gastric juice, as gastritis, stomach ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellisn syndromes.
Have, this compound can be used for treating the gastrointestinal disorders of wishing to suppress the stomachial secretion effect, such as stomach ulcer patient and acute upper gastrointestinal bleeding patient again.They also can be used for intensive nursing care state and the preceding postoperative patient of operation, prevent gastric acid secretion and stress reaction ulcer.
Medicine composition
In yet another aspect, the present invention relates to contain at least a The compounds of this invention or its in treatment acceptable salt as the pharmaceutical composition of activeconstituents.
Compound of the present invention also can use with other activeconstituents compatibility, such as being used for the treatment of or preventing to relate to because the infection that people's stomach mucous membrane Hp causes.These other activeconstituentss can be anti-microbial agents, specifically have:
Beta-Lactam antibiotics is as amoxycillin, penbritin, Glaxo), cefaclor or Cefixime Micronized (cefixime); Perhaps
Junket thing in the big ring is as erythromycin or clarithromycin (clarithromycin); Perhaps
Tetracyclines is as tsiklomitsin or doxycycline; Perhaps
Aminoglycosides is as gentamicin, kantlex or Amikacin Sulphate; Perhaps
Quinolones (quinolones) is as norfloxicin, Ciprofloxacin (ciprofloxacin) and enoxacin (enoxacin); Perhaps
Other class is as Metronidazole plain BP.98 99, furadantin or paraxin;
The perhaps preparation of bismuth-containing salt such as alkali formula bismuth citrate, bismuth subsalicylate, Bismuth Subcarbonate, Vikaline or basic bismuth gallate.
For carrying out clinical use, with the The compounds of this invention preparation become for oral, rectum, intestines are outer or the reagent combination of other administering mode.Reagent combination also contains the acceptable composition of one or more medicines simultaneously containing The compounds of this invention.Carrier can be solid, semisolid or liquid diluent shape, also can be capsule.These pharmaceutical preparations are another targets of the present invention.The consumption of active compound generally is 0.1～95% of a weight of formulation, is preferably 0.2～20% of intestines external preparation weight, is 1～50% of oral preparations.
When preparation contains the formula of medicine of the The compounds of this invention that is oral preparations unit's shape, selected compound can become phase-splitting to mix with solid, powder, such as lactose, sucrose, Sorbitol Powder, mannitol, starch, amylopectin, derivatived cellulose, gelatin or other composition that is suitable for, also can mix with disintegrating agent and lubricant such as Magnesium Stearate, calcium stearate, Stearyl alcohol, sodium fumarate (sodium steryl fumarate) and polyethylene glycol wax.Then mixture is processed into particle or tablet forming.Can be that The compounds of this invention, vegetables oil, fat or other mixture that is suitable for the carrier of soft gelatin capsule are made soft gelatin capsule also with containing active compound.Hard gelatin capsule can contain the active ingredient composition granule.Hard gelatin capsule also can contain the pressed powder composition when containing active compound, as lactose, sucrose, Sorbitol Powder, mannitol, yam starch, W-Gum, amylopectin, derivatived cellulose or gelatin.
The dose unit of rectal administration can be made into the preparation of following form:
(ⅰ) contain and the neutral fat base-material suppository of blended actives mutually;
(ⅱ) contain with vegetables oil, paraffin oil or other and be suitable for use as the gelatin rectal capsule carrier
The gelatin rectal capsule of phase blended actives;
(ⅲ) ready-made little enema; Perhaps
The slight irrigation intestines prescription of (ⅳ) before administration, preparing again with appropriate solvent
Oral liquid can be mixed with syrup or suspension, and such as the solution or the suspension that contain activeconstituents 0.2～20% (weight), rest part is the mixture of sucrose or sugar alcohol and ethanol, water, glycerine, propylene glycol and polyoxyethylene glycol.If needed, such liquid preparation can contain tinting material, flavouring agent, asccharin and carboxymethyl cellulose or other thickening material.Oral liquid also can be prepared into dry powder, dashes with appropriate solvent before taking and joins.
Parenterai administration solution can be mixed with The compounds of this invention can be by the solution that is subjected in the solvent in pharmacy, and its concentration is preferably 0.1～10% (weight).This type of solution also can contain stabilization component and/or buffer components, and disperses to become the unitary dose that is ampoule or bottle.Parenterai administration solution also can be mixed with dry preparation, dashes with appropriate solvent immediately before the use and joins.
The typical per daily dose of actives changes in wide range, and this will depend on various factors, such as each patient's individual demand, route of administration and kinds of Diseases.In general, oral and dosage parenterai administration is 5～1000 milligrams of activess every day.
Embodiment
1. the preparation of The compounds of this invention
Embodiment 1
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
The mixture of 0.67 gram (2.1 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 0.24 gram (2.3 mmole) Ortho Toluidine is heated to 55 ℃ in acetonitrile, and stirred 3.5 hours.Solvent evaporated is also distributed residue between methylene dichloride and saturated sodium bicarbonate solution.With the dried over sodium sulfate organic layer and evaporate it.Develop this residue with Di Iso Propyl Ether.Filter out sedimentary product and with Di Iso Propyl Ether washing, obtain the title compound of 0.55 gram (66%).( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.84(m,2H),2.25(s,3H),2.35(s,3H),3.10(m,4H),4.34(t,2H),6.89(d,1H),6.95-7.15(m,5H),7.27(d,1H),9.26(s,1H),11.84(s,1H).
Embodiment 2
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
0.15 gram (0.38 mmole) 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 3 milliliters of methylene dichloride and is cooled to-20 ℃.Drip the solution of m-CPBA in 1 milliliter of methylene dichloride of 0.089 gram (0.36 mmole) 71%.Allow temperature rise to room temperature, then this solution of stirring at room 15 minutes.Wash this reaction mixture with saturated sodium bicarbonate solution.Use the dried over sodium sulfate organic layer, and with it evaporation, with 10: 1 methylene dichloride: methyl alcohol went out 0.064 gram (41%) required product as the elutriant chromatographic separation.
( 1H-NMR,300MHz,CDCl 3)1.04(t,3H),1.82(m,2H),2.34(s,3H),2.80(s,3H),3.08(t,2H),3.21(m,1H),3.44(m,1H),4.62(m,2H),6.89(d,1H),6.94-7.16(m,5H),7.28(d,1H),9.20(s,1H),11.82(s,1H).
Embodiment 3
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline of 0.037 gram (0.092 mmole) is dissolved in 15 milliliters of methylene dichloride, and is cooled to-20 ℃.Drip the solution of m-CPBA in 0.5 milliliter of methylene dichloride of 0.047 gram (0.19 mmole) 71%.Allow temperature rise to room temperature, then in room temperature with this solution stirring 30 minutes, wash this organic layer with saturated aqueous sodium carbonate.With the dried over sodium sulfate organic layer and with its evaporation.Develop with diisopropyl ether, make the product crystallization.Use methylene dichloride: vinyl acetic monomer (1: 1) is as elutriant, becomes pure vinyl acetic monomer when the end precipitation is carried out after chromatogram purifies, and isolates the title compound of 0.022 gram (56%).( 1H-NMR,500MHz,CDCl 3)1.07(t,3H),1.84(m,2H),2.35(s,3H),3.10(t,2H),3.39(s,3H),3.62(t,2H),4.61(t,2H),6.89(d,1H),6.94-7.17(m,5H),7.28(m,1H),9.15(s,1H),11.86(s,1H).
Embodiment 4
Preparation 3-butyryl-4-(2-isopropyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
With the mixture heating up to 150 of 400 milligrams of (1.23 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 1.0 gram (7.4 mmole) 2-isopropyl anilines ℃ 30 minutes.Use CHCl 3Dilute this mixture and use the 2N hcl as extraction agent.Wash organic phase with saturated sodium bicarbonate solution.Use Na 2SO 4Dry organic layer also evaporates it.Use SiO 2: CH 2Cl 2: 95: 5 pairs of residues of MeOH carry out chromatogram purifies, and obtains 340 milligrams of (80.5%) desired products.( 1H-NMR,300MHz,CDCl 3):1.0(t,3H),1.1(d,3H),1.2(d,3H),1.75(m,2H),2.15(s,3H),3.1(m,3H),3.2(t,2H),4.3(t,2H),6.8(d,1H),7.0-7.2(m,4H),7.4-(m,2H),9.4(d,1H).
Embodiment 5
Preparation 3-butyryl-4-(2-isopropyl phenyl amino)-8-(2-methylsulfinyl base oxethyl) quinoline
3-butyryl-4-(2-isopropyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline of 0.22 gram (0.52 mmole) is dissolved in 15 milliliters of methylene dichloride, and is added to 0.093 gram NaHCO 3In the mixture in 15 ml waters.At 4 ℃ of 71%m-CPBA solution in 7 milliliters of methylene dichloride that drip 0.12 gram (0.50 mmole).Under this temperature, stirred this solution 1 hour.With saturated sodium bicarbonate solution washing reaction mixture.Use Na 2SO 4Dry organic layer also evaporates it.Use methylene dichloride: methyl alcohol as elutriant carries out chromatogram at 10: 1 purifies, and obtains the required product of 0.130 gram (57%).( 1H-NMR,300MHz,CDCl 3).1.0(t,3H),1.3(m,6H),1.8(m,2H),2.78(s,3H),3.08(t,2H),3.2(m,6H),3.35(m,1H),3.45(m,1H),4.6(m,2H),6.82(d,1H),6.86(t,1H),7.05(m,3H),7.2 (t,1H),7.38(d,1H),9.18(s,1H),11.8(s,1H).
Embodiment 6
Preparation 3-butyryl-4-(2-isopropyl phenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
The mixture that 0.22 solution and 0.186 of 3-butyryl-4-(2-isopropyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline in 15 milliliters of methylene dichloride that restrains (0.52 mmole) is restrained the solution formation of sodium bicarbonate (2.2 mmole) in 15 ml waters is cooled to 4 ℃.Drip the solution of m-CPBA in 7 milliliters of methylene dichloride of 0.24 gram (1.0 mmole) 70%.4 ℃ stir 1 hour after. use Na 2SO 4Dry organic layer, and evaporate it.With chromatogram (SiO 2CH 2Cl 2: MeOH 90: 10) purify, obtain the required product of 16 milligrams (6.8%).( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.2(m,6H),1.8(m,2H),3.1(t,2H),3.35(s,3H),3.45(m,1H),3.65(m,2H),4.6(m,2H),6.85(d,2H),6.9-7.1(m,4H),7.4(d,1H),9.1(s,1H),11.8(s,1H).
Embodiment 7
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
3-propionyl-4-chloro-8-(2-methylthio group ethoxy base) quinoline of 0.60 gram (1.9 mmole) and the mixture of 0.25 gram (2.3 mmole) Ortho Toluidine are heated to 55 ℃ and stirred 3.5 hours in acetonitrile.Steam solvent, residue is distributed between ethylene dichloride and 10% sodium carbonate solution.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: vinyl acetic monomer 60: 40) purify, obtain the title compound of 0.45 gram (61%).( 1H-NMR,300MHz,CDCl 3)1.26(t,3H),2.21(s,3H),2.33(s,3H),3.06(t,2H),3.10(q,2H),4.33(t,2H),6.87(d,1H),6.96-7.12(m,5H),7.25(d,1H),9.26(s,1H),11.78(s,1H).
Embodiment 8
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl base oxethyl) quinoline is made a din
0.10 gram (0.26 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 5 milliliters of methylene dichloride.Add 45 milligrams of NaHCO 3Solution in 5 ml waters.Mixture is cooled to 4 ℃.Drip 71% the solution of m-CPBA in 5 milliliters of methylene dichloride of 0.062 gram (0.25 mmole).After 1 hour, use saturated NaHCO 2～4 ℃ of stirrings 3This organic layer of solution washing is used Na 2SO 4Dry organic layer and evaporation.Chromatogram (SiO 2CH 2Cl 2: ethanol 90: 10) purify, obtain the required product of 50 milligrams (48%).( 1H-NMR,300MHz,CDCl 3)1.26(t,3H),2.33(s,3H),278(s,3H),3.10-3.50(m,4H),4.61(m,2H),6.85(d,1H),6.92-7.11(m,5H),7.28(d,1H),9.18(s,1H),11.81(s,1H).
Embodiment 9
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
0.12 gram (0.32 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 5 milliliters of methylene dichloride.Add 110 milligrams of NaHCO 3Solution in 10 ml waters.This mixture is chilled to 4 ℃.Drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 0.17 gram (0.69 mmole) 71%.Used later saturated NaHCO in 1 hour 2～4 ℃ of stirrings 3This organic layer of solution washing.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: ethyl acetate 50:50) purification obtains the title compound of 0.060 gram (45%).( 1H-NMR,300MHz,CDCl 3)1.26(t,3H),2.34(d,3H),3.15(q,2H),3.37(s,3H),3.61(t,2H),4.58(t,2H),6.86(d,1H),6.95-7.11(m,5H),7.26(d,1H),9.13(s,1H),11.81(s,1H).
Embodiment 10
Preparation 3-propionyl-4-(2-ethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline
3-propionyl-4-chloro-8-(2-methylthio group ethoxy base) quinoline of 0.093 gram (0.34 mmole) and the mixture of 0.048 gram (0.39 mmole) 2-ethylaniline are heated to 65 ℃ in 1 milliliter of acetonitrile, and stirred 4.0 hours.Boil off solvent, at methylene dichloride and saturated NaHCO 3Distribute residue between the solution.Use Na 2SO 4Dry organic phase is also evaporated it.With chromatogram (SiO 2Vinyl acetic monomer) purification residue obtains the required product of 40 milligrams (30%).( 1H-NMR,300MHz,CDCl 3)1.22-1.30(m,6H),2.22(s,3H),2.76(q,2H)3.06(t,2H),3.15(q,2H),4.34(t,2H),6.82(d,1H),6.91-7.06(m,2H),7.14(m,1H),7.28(m,1H),9.21(s,1H),11.83(s,1H).
Embodiment 11 and 12
Preparation 3-propionyl-4-(2-ethylphenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline (embodiment 11) and 3-propionyl-4-(2-ethylphenyl amino)-8-(2-sulfonyloxy methyl base oxethyl) quinoline (embodiment 12)
0.022 gram (0.056 mmole) 3-propionyl-4-(2-ethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 0.7 milliliter of methylene dichloride.Add 12 milligrams of NaHCO 3Solution in 0.7 ml water.This mixture is cooled to 4 ℃.Drip the solution of m-CPBA in 0.5 milliliter of methylene dichloride of 0.017 gram (0.07 mmole) 71%.Use saturated NaHCO 2～4 ℃ of stirrings after 1 hour 3This organic layer of solution washing.Use Na 2SO 4Dry organic layer also evaporates it.With chromatogram (SiO 2CH 2Cl 2: MeOH 90: 10) purify, obtain 8 milligrams (35%) according to the compound of embodiment 11 and 10 milligrams (42%) compound according to embodiment 12.Embodiment 11 ( 1H-NMR, 300MHz, CDCl 3): 1.25 (m, 6H), 2.73-2.81 (m, 5H), 3.15 (q, 2H), 3.22 (m, 1H), 3.41-3.49 (m, 1H), 4.62 (m, 2H), 6.84 (d, 1H), 6.93-7.19 (m, 5H), 7.31 (d, 1H), 9.19 (s, 1H), 11.88 (s, 1H). embodiment 12 ( 1H-NMR, 300MHz, CDCl 3): 1.29 (m, 6H), 2.77 (q, 2H), 3.16 (q, 2H), 3.37 (s, 3H), 3.61 (t, 2H), 4.60 (t, 2H), 6.85 (d, 1H), 6.94-7.20 (m, 5H), 7.31 (d, 1H) .9.14 (s, 1H), 11.90 (s, 1H).
Embodiment 13
Preparation 3-butyryl-4-(4-fluoro-2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
The mixture of 2.75 gram (82 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 1.34 gram (10.7 mmole) 4-fluoro-2-aminotoluenes was refluxed 8 hours in 20 milliliters of acetonitriles.With the cooling of this solution and filter out 1.52 gram crystallized products.Evaporated filtrate is also used chromatogram (SiO 2CH 2Cl 2: MeOH 95: 5) purify, obtain the required product of 0.4 gram.Total yield 1.92 grams (57%).( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.85(m,2H),2.20(s,3H),2.30(s,3H),3.05(m,4H),4.35(t,2H),6.75-6.90(m,2H),7.00(m,4H),9.20(s,1H),11.80(s,1H).
Embodiment 14 and 15
Preparation 3-butyryl-4-(4-fluoro-2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline (embodiment 14) and 3-butyryl-4-(4-fluoro-2-aminomethyl phenyl amino)-8-(2-sulfonyloxy methyl oxyethyl group) quinoline (embodiment 15)
1.6 gram (3.88 mmole) 3-butyryl-4-(4-fluoro-2-aminomethyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline are dissolved in 35 milliliters of methylene dichloride.Add 36 milliliters of 0.3M NaHCO 3Solution.This mixture is cooled to 4 ℃.Drip the solution of m-CPBA in 16 milliliters of methylene dichloride of 1.22 gram (5.04 mmoles) 70%.After 1 hour, use 0.3M NaHCO 2～4 ℃ of stirrings 3This organic layer of solution washing.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: MeOH 95: 5) purify obtain 1.55 grams (93%) according to the compound of embodiment 14 and the compound according to embodiment 15 of 0.31 gram (18%).Embodiment 14:( 1H-NMR, 300MHz, CDCl 3) 0.95 (t, 3H), 1.75 (m, 2H), 2.20 (s, 3H), 2.70 (s, 3H), 3.00 (t, 2H), 3.10 (m, 1H), 3.30-3.40 (m, 1H), 4.50 (m, 2H), 6.70 (m, 1H), 6.75 (m, 1H), 6.85-6.95 (m, 3H), 7.00 (m, 1H), 9.10 (s, 1H), 11.85 (s, 1H). embodiment 15:( 1H-NMR, 300MHz, CDCl 3): 1.05 (t, 3H), 1.80 (m, 2H), 2.30 (s, 3H), 3.10 (t, 2H), 3.40 (s, 3H), 3.60 (t, 2H), 4.60 (t, 2H), 6.75-6.80 (m, 1H), 6.85-6.90 (m, 1H), 6.95-7.05 (m, 4H), 9.15 (s, 1H), 11.85 (s, 1H).
Embodiment 16
Preparation 3-propionyl-4-(2-isopropyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
305 milligrams of (1 mmole) 3-propionyl-4-chloro-8-(2-methylthio group ethoxy base) quinoline made a din and the mixture of 1 milliliter of 2-isopropyl aniline refluxes in 25 milliliters of acetonitriles and spends the night.Boil off solvent and at methylene dichloride and saturated NaHCO 3Distribute between the solution.Use Na 2SO 4Dry organic layer also evaporates it.With preparation thin-layer chromatography (methylene dichloride: vinyl acetic monomer 1: 1) residue is purified, obtain the required product of 30 milligrams (8%).( 1H-NMR,300MHz,CDCl 3)1.3(m,9H),2.25(s,3H),3.05(t,2H),3.15(q,2H),3.4(m,1H),4.3(t,2H),6.8(d,1H),7.0(m,4H),7.2(t,1H),7.4(d,1H),9.2(s,1H).
Embodiment 17
Preparation 3-butyryl-4-(2-ethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline
The mixture of 3.69 gram (9.84 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 1.55 gram (12.8 mmole) 2-ethylaniline was refluxed 6 hours in 20 milliliters of acetonitriles.Evaporate this solution, with chromatogram (SiO 2CH 2Cl 2: MeOH 97: 3) purification obtains 2.79 gram (69%) required products.( 1H-NMR,300MHz,CDCl 3)1.00(t,3H),1.25(t,3H),1.80(m,2H),2.20(s,3H),2.80(m,2H),3.10(m,4H),4.35(t,2H),6.85(m,1H),6.90-7.10(m,4H),7.15(t,1H),7.30(m,1H),9.20(s,1H).
Embodiment 18 and 19
Preparation 3-butyryl-4-(2-ethylphenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline (embodiment 18) and 3-butyryl-4-(2-ethylphenyl amino)-8-(2-sulfonyloxy methyl base oxethyl) quinoline (embodiment 19)
1.98 gram (4.85 mmole) 3-butyryl-4-(2-ethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline are dissolved in 40 milliliters of methylene dichloride.Add 45 milliliters of 0.3M NaHCO 3Solution.Mixture is cooled to 4 ℃.Drip the solution of m-CPBA in 20 milliliters of methylene dichloride of 1.54 gram (6.31 mmoles) 70%.After 1 hour, use the NaHCO of 0.3M 2～4 ℃ of stirrings 3This organic layer of solution washing Na 2SO 4Dry organic layer also evaporates it, chromatogram (SiO 2CH 2Cl 2: MeOH 97: 3) purification obtains the compound of 0.62 gram (30%) embodiment 18 and the compound of 0.39 gram (18%) embodiment 19.Example18:( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.30(t,3H),1.85(m,2H),2.75(m,2H),2.85(5,3H),3.05(t,2H),3.20-3.30(m,1H),3.40-3.50(m,1H),4.65(m,2H),6.85(m,1H),6.90-7.00(m,1H),7.05-7.10(m,3H),7.15(t,1H),7.30(m,1H),9.20(s,1H),11.95(s,1H).Example19:( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.30(t,3H),1.85(m,2H),2.75(m,2H),3.10(t,2H),3.40(s,3H),3.65(m,2H),4.60(m,2H),6.85(d,1H),6.95-7.10(m,4H),7.20(t,1H),7.30(m,1H),9.10(s,1H).
Embodiment 20
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-rosickyite base oxethyl) quinoline
2.5 gram (7.40 mmole) 3-propionyl-4-chloro-8-(2-rosickyite base oxethyl) quinoline and 0.95 gram (8.86 mmole) Ortho Toluidine were refluxed 2 hours in 10 milliliters of acetonitriles.Evaporating solvent and with residue at methylene dichloride and 10%Na 2CO 3Distribute between the solution.With the dried over sodium sulfate organic layer and evaporate it.(methylene dichloride: this crude product of purifying vinyl acetic monomer 80: 20) obtains 1.8 gram (60%) title compounds with column chromatography.( 1H-NMR,300MHz,CDCl 3)1.00(t,3H),1.28(t,3H)1.66(m,2H),2.35(s,3H)2.62(t,2H),3.09(t,2H),3.14(q,2H),4.32(t,2H),6.80-7.25(m,7H),9.22(s,1H),11.76(s,1H).
Embodiment 21
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(the 2-third sulfinyl oxyethyl group) quinoline
0.5 gram (1.22 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-rosickyite base oxethyl) quinoline is dissolved in 10 milliliters of methylene dichloride.Add 250 milligrams of (3.0 mmole) NaHCO 3Solution in 10 ml waters.This mixture is cooled to 2～4 ℃.In 10 minutes, drip the solution of m-CPBA in 10 milliliters of methylene dichloride of 295 milligrams of (1.20 mmoles) 70%.Allow temperature rise to room temperature, and under this temperature, stirred this mixture 30 minutes.Use Na 2SO 4Dry this organic layer.(methylene dichloride: purification residue ethanol 90: 10) obtains the title compound of 380 milligrams (73%) with column chromatography.( 1H-NMR,300MHz,CDCl 3)1.11(t,3H),1.28(t,3H),1.87(m,2H),2.35(s,3H),2.89(m,2H),3.10-3.20(m,3H),3.40(m,1H),4.63(q,2H),6.90-7.40(m,7H),9.19(s,1H),11.85(s,1H).
Embodiment 22
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-third nyl ethoxy) quinoline
500 milligrams of (1.22 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(2-rosickyite base oxethyl) quinoline is dissolved in 10 milliliters of methylene dichloride.Be added in 500 milligrams of (5.95 mmole) NaHCO in 10 ml waters 3Solution.This mixture is cooled to 2～4 ℃.Drip the solution of m-CPBA in 10 milliliters of methylene dichloride of 600 milligrams of (2.43 mmoles) 70%.Allow temperature be raised to room temperature, and under this temperature, continue to stir 30 minutes.The separate dichloromethane layer also washes with water.Use Na 2SO 4Dry organic layer also evaporates it.With column chromatography (methylene dichloride: this thick product of purifying vinyl acetic monomer 50: 50).Obtain 340 milligrams of (63%) title compounds.( 1H-NMR,300MHz,CDCl 3)1.13(t,3H),1.27(t,3H),1.96(m,2H),2.35(s,3H),3.16(q,2H),3.47(t,2H),3.58(t,2H),4.58(t,2H),6.85-7.25(m,7H),9.12(s,1H),11.81(s,1H).
Embodiment 23
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-rosickyite base propoxy-) quinoline
2.0 gram (5.7 mmole) 3-propionyl-4-chloro-8-(rosickyite base propoxy-) quinoline and 0.7 gram (6.5 mmole) Ortho Toluidine were refluxed 2 hours in 10 milliliters of acetonitriles.Boil off solvent, and with residue at methylene dichloride and 10%Na 2CO 3Distribute between the solution.Use Na 2SO 4Dry organic layer also evaporates it.With column chromatography (methylene dichloride: the thick product of purifying vinyl acetic monomer 70: 30).Obtain 1.3 gram (54%) title compounds.( 1H-NMR,300MHz,CDCl 3)0.94(t,3H),1.26(t,3H),1.57(m,2H),2.25(m,2H),234(s,3H),2.49(t,2H),2.75(t,2H),3.15(q,2H),4.27(t,2H)6.83-7.23(m,7H),9.22(s,1H),11.73(s,1H).
Embodiment 24
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(the 3-third sulfinyl propoxy-) quinoline
200 milligrams of (0.47 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-rosickyite base propoxy-) quinoline is dissolved in 5 milliliters of methylene dichloride.Be added in the solution of 80 milligrams of (0.95 mmole) sodium bicarbonates in 5 ml waters.This mixture is cooled to 2～4 ℃.In 10 minutes, drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 115 milligrams of (0.47 mmoles) 70%.Allow temperature heat up, and at room temperature mixture was stirred 30 minutes.The separate dichloromethane layer also washes with water.Use Na then 2SO 4Dry organic layer also evaporates it.(methylene dichloride: alcohol 95: 5) the thick product of purifying obtains 160 milligrams (77% title compounds) with column chromatography.( 1H-NMR,300MHz,CDCl 3)1.06(t,3H),1.27(t,3H),1.79(m,2H),2.33(s,3H),2.49(m,2H),2.60-2.80(m,3H),2.93(m,1H),3.17(q,2H),4.34(m,2H),6.85-7.30(m,7H),9.26(s,1H),12.01(s,1H).
Embodiment 25
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(the 3-third sulphonyl propoxy-) quinoline
200 milligrams of (0.47 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-rosickyite base propoxy-) quinoline is made a din and is dissolved in 5 milliliters of methylene dichloride.Add the solution of 160 milligrams of (1.90 mmole) sodium bicarbonates in 5 ml waters.This mixture is cooled to 2～4 ℃.In 5 minutes, drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 230 milligrams of (0.94 mmoles) 70%.Allow temperature heat up, and at room temperature stirred the mixture 30 minutes.The separate dichloromethane layer also washes with water.Use Na then 2SO 4Dry organic layer also evaporates it.With column chromatography (SiO 2Methylene dichloride: purification crude product vinyl acetic monomer 50: 50) obtains 110 milligrams of (51%) title product.( 1H-NMR,300MHz,CDCl 3):1.06(t,3H),1.28(t,3H),1.88(m,2H),2.35(s,3H),2.50(m,2H),2.97(t,2H),3.16(q,2H),3.32(t,2H),4.35(t,2H),6.85-7.30(m,7H),9.19(s,1H),11.78(s,1H).
Embodiment 26
Preparation 3-butyryl-4-(4-hydroxy-2-methyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
The mixture of 2.48 gram (6.63 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 1.06 gram (8.62 mmole) 4-hydroxy-2-methyl aniline was refluxed 8 hours in 20 milliliters of acetonitriles.Evaporation reaction mixture, chromatogram (SiO 2CH 2Cl 2: purification residue MeOH 95: 5) obtains 1.22 gram (45%) required products.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80(m,2H),2.20(s,6H),3.00-3.10(m,4H),4.30(m,2H),6.55(m,1H),6.75-6.85(m,2H),6.95(m,2H),7.00-7.10(m,1H),9.15(s,1H).
Embodiment 27 and 28
Preparation 3-butyryl-4-(4-hydroxy-2-methyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline (embodiment 27) and 3-butyryl-4-(4-hydroxy-2-methyl phenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline (embodiment 28)
1.06 gram (2.59 mmole) 3-butyryl-4-(4-hydroxy-2-methyl phenyl amino)-8-(2-methylthio group ethoxy base) quinoline are dissolved in 25 milliliters of methylene dichloride.Add 24 milliliters of 0.3M NaHCO 3Solution.This mixture is cooled to 4 ℃.Drip the solution of m-CPBA in 15 milliliters of methylene dichloride of 0.82 gram (3.37 mmole) 70%.2～4 ℃ stir 1.5 hours after. use 0.3M NaHCO 3The solution washing organic layer.Use Na 2SO 4Dry organic layer also evaporates it.Use vinyl acetic monomer on silica gel chromatography: methylene dichloride as elutriant obtains embodiment 27 compounds of 0.4 gram (35%) at 1: 1; Use methylene dichloride again: methyl alcohol (9: 1) wash-out, obtain 0.52 the gram (47%) embodiment 28 compound.Embodiment 27:( 1H-NMR, 300MHz, CDCl 3) 1.05 (t, 3H), 1.80 (m, 2H), 2.20 (s, 3H), 2.75 (s, 3H), 3.05 (m, 2H), 3.10-3.20 (m, 1H), 3.40-3.50 (m, 1H), 4.55 (m, 2H), 6.55-6.60 (m, 1H), 6.75-6.80 (m, 2H), 6.90-6.95 (m, 1H), 7.00-7.10 (m, 2H), 9.15 (s, 1H). embodiment 28:( 1H-NMR, 300MHz, CDCl 3) 1.05 (t, 3H), 1.80 (m, 2H), 2.25 (s, 3H), 3.05 (t, 2H), 3.35 (s, 3H), 3.60 (m, 2H), 4.55 (m, 2H), 6.55-6.60 (m, 1H), 6.75 (m, 1H), 6.80-6.85 (m, 1H), 6.95-7.05 (m, 2H), 7.10 (m, 1H), 9.10 (s, 1H).
Embodiment 29
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline is made a din
The mixture of 0.8 gram (2.5 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 0.47 gram (3.7 mmole) 2-chloroaniline is heated to 90 ℃ in 12 milliliters of toluene, and stirred 3.0 hours.After being cooled to room temperature, add methylene dichloride and water.Use saturated NaHCO 3Solution this mixture that neutralizes.Use Na 2SO 4Dry organic layer.Develop with isopropyl ether, obtain 0.84 gram (81%) required compound.( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.80-1.90(m,2H),2.25(s,3H),3.10-3.15(m,4H),4.35-4.40(m,2H),6.80-6.90(m,1H),7.05-7.15(m,5H),7.45-7.50(m,1H),9.30(s,1H),11.55(s,1H)
Embodiment 30
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
0.34 gram (0.82 mmole) 3-butyryl-4-(2-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 4 milliliters of methylene dichloride.Add 2 ml waters and 1.37 milliliter of 5% chlorine bleach liquor, stirred this mixture 2 hours.Add a 0.5 milliliter of clorox again, and continue to stir 2 hours.Use Na 2SO 4Dry organic layer also evaporates it.Carry out crystallization with vinyl acetic monomer and isopropyl ether, obtain 0.25 gram (71%) title compound.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.75-1.90(m,2H),2.85(s,3H),3.10(t,2H),3.20-3.30(m,1H),3.45-3.55(m,1H),4.60-4.70(m,2H),6.80-6.90(m,1H),7.00-7.20(m,5H),7.40-7.50(m,1H),9.30(s,1H),11.60(s,1H)
Embodiment 31
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
With 0.4 gram (0.96 mmole) 3-butyryl-4-(2-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline solution and 5 milliliters of saturated NaHCO in 5 milliliters of methylene dichloride 3The mixture of solution is cooled to 4 ℃.Drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 0.48 gram (1.97 mmole) 70%.After 1 hour, use saturated NaHCO 4 ℃ of stirrings 3The solution washing organic layer is used Na then 2SO 4Drying, and evaporate it.With the isopropyl ether development, obtain 0.28 gram (65%) required product.( 1H-NMR,300MHZ,CDCl 3)1.05(t,3H),1.75％1.90(m,2H),3.10(t,2H),3.40(s,3H),3.60-3.70(m,2H),4.60-4.70(m,2H),6.85-6.90(m,1H),7.00-7.20(m,5H),7.45-7.50(m,1H),9.20(s,1H),11.65(s,1H)
Embodiment 32
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(2-methylthio group ethoxy base) quinoline
With the mixture heating up to 90 of mixture in 12 milliliters of toluene of 0.8 gram (2.5 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 0.45 gram (3.7 mmole) 2-anisidine ℃ and stirred 3.0 hours.After being cooled to room temperature, add methylene dichloride and water.With saturated NaHCO 3The solution neutralise mixt.Use Na 2SO 4Dry organic layer also evaporates it.With the isopropyl ether development, obtain 0.80 gram (77%) required product.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.75-1.90(m,2H),2.30(s,3H),3.05-3.15(m,4H),3.85(s,3H),4.35-4.40(m,2H),6.75-6.85(m,1H),6.90-7.15(m,5H),7.25-7.30(m,1H),9.25(s,1H),11.55(s,1H)
Embodiment 33
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
0.35 gram (0.85 mmole) 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 4 milliliters of methylene dichloride.Add 2 ml waters and 1.42 milliliter of 5% chlorine bleach liquor and stirred this mixture 2 hours.Add 0.5 milliliter of clorox of another part again and continue stirring 2 hours.Use Na 2SO 4Dry organic layer also evaporates it.With vinyl acetic monomer and isopropyl ether crystallization residue, obtain 0.32 gram (88%) title compound.( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.75-1.90(m,2H),2.80(s,3H),3.05-3.10(m,2H),320-3.30(m,1H),3.45-3.55(m,1H),3.80(s,3H),4.60-4.70(m,2H),6.80-6.85(m,1H),6.90-7.20(m,5H),7.30-7.35(m,1H),9.20(s,1H),11.60(s,1H)
Embodiment 34
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
With 0.35 gram (0.85 mmole) 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(2-methylthio group ethoxy base) quinoline solution and 5 milliliters of saturated NaHCO in 5 milliliters of methylene dichloride 3The mixture of solution is cooled to 4 ℃.Drip the solution of 0.43 gram (1.74 mmole) 70%m-CPBA in 5 milliliters of methylene dichloride.After stirring 1 hour under 4 ℃, use saturated NaHCO 3The solution washing organic layer is used Na then 2SO 4Drying is also evaporated it.With the isopropyl ether development, obtain 0.28 gram (65%) required product.( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.75-1.90(m,2H),3.05-3.10(m,2H),3.40(s,3H),3.60-3.70(m,2H),3.85(s,3H),4.60-4.65(m,2H),6.80-6.85(m,1H),6.90-7.20(m,5H),7.30-7.35(m,1H),9.15(s,1H),11.60(s,1H)
Embodiment 35
Preparation 3-butyryl-4-(2,4-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline
With 0.8 gram (2.5 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline and 0.45 gram (3.7 mmole) 2, the mixture of 4-xylidine is heated to 90 ℃ and stirred 3.0 hours in 12 milliliters of toluene.After being cooled to room temperature, add entry and methylene dichloride.With saturated NaHCO 3Solution this mixture that neutralizes.Use Na 2SO 4Dry organic layer also evaporates it.With the isopropyl ether development, obtain the required product of 0.77 gram (75%).( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.75-1.90(m,2H),2.25(s,3H),2.30(s,3H),2.35(s,3H),3.05-3.15(m,4H),4.30-4.40(m,2H),6.80-6.85(m,1H),6.90-7.10(m,5H),9.20(s,1H),11.85(s,1H)
Embodiment 36
Preparation 3-butyryl-4-(2,4-3,5-dimethylphenyl amino)-8-(2-methylsulfinyl base oxethyl) quinoline
0.34 gram (0.83 mmole) 3-butyryl-4-(2,4-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 4 milliliters of methylene dichloride.Add the aqueous sodium hypochlorite solution of 2 ml waters and 1.39 milliliter 5% and stirred this mixture 2 hours.Add 0.5 milliliter of clorox of another part again, and continue to stir 2 hours.Use Na 2SO 4Dry organic layer also evaporates it.With the isopropyl ether development, obtain 0.32 gram title compound (91%).( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.75-1.90(m,2H),2.30(s,3H),2.35(s,3H),2.80(s,3H),3.05-3.15(m,2H),3.20-3.30(m,1H),3.40-3.55(m,1H),4.60-4.65(m,2H),6.80-6.85(m,1H),6.90-7.15(m,5H),9.15(s,1H).11.85(s,1H)
Embodiment 37
Preparation 3-butyryl-4-(2,4-3,5-dimethylphenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
With 0.33 gram (0.81 mmole) 3-butyryl-4-(2,4-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline solution and 5 milliliters of saturated NaHCO in 5 milliliters of methylene dichloride 3The mixture of solution is cooled to 4 ℃.Drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 0.40 gram (1.66 mmole) 70%.Use saturated NaHCO 4 ℃ of stirrings after 1 hour 3The solution washing organic layer is used Na then 2SO 4Drying is also evaporated it.After with the isopropyl ether development, obtain crystallized product.With chromatogram (SiO 2CH 2Cl 2: MeOH 90: 10) purify, obtain 0.17 gram (48%) required compound ( 1H-NMR, 300MHz, CDCl 3) 1.05 (t, 3H), 1.75-1.90 (m, 2H), 2.30 (s, 3H), 2.35 (5,3H), 3.05-3.15 (m, 2H), 3.40 (s, 3H), 3.60-3.65 (m, 2H), 4.60-4.65 (m, 2H), 6.80-6.85 (m, 1H), 6.90-7.15 (m, 5H), 9.10 (s, 1H), 11.90 (s, 1H)
Embodiment 38
Preparation 3-butyryl-4-(2,6-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline
0.8 gram (2.5 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline is made a din and 0.45 gram (3.7 mmole) 2, and the mixture of 6-xylidine is heated to 90 ℃ in 12 milliliters of toluene, and stirs 3.0 hours.Add methylene dichloride and water after being cooled to room temperature.Use saturated NaHCO 3Solution this mixture that neutralizes.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2Vinyl acetic monomer) purification obtains 0.7 gram (68%) title compound.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.75-1.90(m,2H),2.10(s,6H),2.25(s,3H),3.05-3.15(m,4H),4.30-4.35(m,2H),6.85-7.20(m,6H),9.20(s,1H),12.25(s,1H)
Embodiment 39
Preparation 3-butyryl-4-(2,6-3,5-dimethylphenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
0.33 gram (0.81 mmole) 3-butyryl-4-(2,6-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline is made a din and is dissolved in 4 milliliters of methylene dichloride.Add the aqueous sodium hypochlorite solution of 2 ml waters and 1.7 milliliter 5%, stirred this mixture 3 hours.Use Na 2SO 4Dry organic layer also evaporates it.With the isopropyl ether development, obtain 0.20 gram (58%) title compound.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,2H),2.10(s,3H),2.15(s,3H),2.80(s,3H),3.10-3.15(m,2H),3.20-3.30(m,1H),3.40-3.55(m,1H),4.55-4.65(m,2H),6.85-6.95(m,2H),7.05-7.25(m,4H),9.20(s,1H),12.25(s,1H)
Embodiment 40
Preparation 3-butyryl-4-(2,6-3,5-dimethylphenyl amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
With 0.36 gram (0.88 mmole) 3-butyryl-4-(2,6-3,5-dimethylphenyl amino)-8-(2-methylthio group ethoxy base) quinoline solution and 5 milliliters of saturated NaHCO in 5 milliliters of methylene dichloride 3Mixture be cooled to 4 ℃.Drip the solution of 0.42 gram (1.76 mmole) 70%m-CPBA in 5 milliliters of methylene dichloride.After 1 hour, use saturated NaHCO 4 ℃ of stirrings 3The solution washing organic layer is used Na then 2SO 4Drying is also evaporated it.With obtaining crystallized product after the isopropyl ether development.Chromatogram (SiO 2CH 2Cl 2: MeOH 90: 10) purification is carried out crystallization with vinyl acetic monomer again, finally obtains 0.070 gram (18%) required product.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80-1.95(m,2H),2.10(s,6H),3.05-3.15(m,2H),3.40(s,3H),3.60-3.65(m,2H),4.55-4.60(m,2H),6.85-6.95(m,2H),7.00-7.25(m,4H),9.10(s,1H),12.30(s,1H)
Embodiment 41
Preparation 3-butyryl-4-(2-methyl, 6-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline
0.8 gram (2.5 mmole) 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base) quinoline is made a din and 0.52 gram (3.7 mmole) 2-methyl, and the mixture of 6-chloroaniline is heated to 90 ℃ and stirred 3.0 hours in 12 milliliters of toluene.After being cooled to room temperature, add methylene dichloride and water.Use saturated NaHCO 3Solution this mixture that neutralizes.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2: acetic acid second junket) purification obtains 0.77 gram (72%) title compound.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,2H),2.15(s,3H),2.25(s,3H),3.05-3.15(m,4H),4.30-4.40(m,2H),6.85-6.90(1H),6.90-7.05(m,2H),7.15-7.35(m,3H),9.20(s,1H),12.15(s,1H)
Embodiment 42
Preparation 3-butyryl-4-(2-methyl, 6-chloro-phenyl-amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
0.35 gram (0.82 mmole) 3-butyryl-4-(2-methyl, 6-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline is dissolved in 4 milliliters of methylene dichloride.Add the chlorine bleach liquor of 2 ml waters and 1.7 milliliter 5% and this mixture was stirred 3 hours.Use Na 2SO 4Dry organic layer also evaporates it.With acetic acid second junket crystallization residue, obtain 0.10 gram (27%) title compound.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,2H),2.15(m,3H),2.85(m,3H),3.10-3.15(m,2H),3.20-3.30(m,1H),3.40-3.55(m,1H),4.55-4.70(m,2H),6.85-7.00(m,2H),7.05-7.10(m,1H),7.15-7.35(m,3H),9.20(s,1H),12.20(s,1H)
Embodiment 43
Preparation 3-butyryl-4-(2-methyl, 6-chloro-phenyl-amino)-8-(2-methylsulfonyl oxyethyl group) quinoline
With 0.34 gram (0.79 mmole) 3-butyryl-4-(2-methyl, 6-chloro-phenyl-amino)-8-(2-methylthio group ethoxy base) quinoline solution and 5 milliliters of saturated NaHCO in 5 milliliters of methylene dichloride 3The mixture of solution is cooled to 4 ℃.Drip the solution of m-CPBA in 5 milliliters of methylene dichloride of 0.38 gram (1.58 mmole) 70%.Use saturated NaHCO 4 ℃ of stirrings after 1 hour 3The solution washing organic layer is used Na then 2SO 4Drying is also evaporated it.Obtain 0.11 gram (30%) required product with the vinyl acetic monomer crystallization.( 1H-NMR,300MHz,CDCl 3)1.05(t,3H),1.80-1.95(m,2H),2.15(s,3H),3.05-3.15(m,2H),3.40(s,3H),3.60－3.70(m,2H),4.55-4.65(m,2H),6.90-7.05(m,3H),7.15-7.25(m,2H),7.30-7.35(m,1H),9.15(s,1H),12.20(s,1H)
Embodiment 44
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-methylthio group propoxy-) quinoline is made a din
1.2 gram (3.71 mmole) 3-propionyl-4-chloro-8-(3-methylthio group propoxy-) quinoline were refluxed 100 minutes in 18 milliliters of acetonitriles with 0.795 gram (7.42 mmole) Ortho Toluidine.Boil off solvent use then column chromatography (methylene dichloride: purification residue methyl alcohol 100: 3), obtain 1.45 the gram (99%) title compounds.( 1H-NMR,300MHz,CDCl 3)1.3(t,3H),2.15(s,3H),2.2-2.3(m,2H),2.33(s,3H),2.75(t,2H),3.15(q,2H),4.28(t,2H),6.83-6.92(m,1H),6.95-7.18(m,5H),7.25-7.33(m,1H),9.25(s,H),11.75(s,1H).
Embodiment 45 and 46
Preparation 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-methylsulfinyl propoxy-) quinoline (embodiment 45) and 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-methylsulfonyl propoxy-) quinoline (embodiment 46)
1.03 gram (2.611 mmole) 3-propionyl-4-(2-aminomethyl phenyl amino)-8-(3-methylthio group propoxy-) quinoline are dissolved in 30 milliliters of methylene dichloride.Add 26 milliliters of (7.83 mmole) 0.3M NaHCO 3Solution.This mixture is cooled to 4 ℃.In 45 minutes, drip the solution of m-CPBA in 27 milliliters of methylene dichloride of 0.895 gram (3.66 mmole) 70.5%., separate organic phase and use 0.3M NaHCO after 30 minutes 4 ℃ of stirrings 3Solution washing.Use Na 2SO 4Dry organic layer also evaporates it.Column chromatography (SiO 2CH 2Cl 2: MeOH 100: 3 and 100: 6) purify, obtain the compound of 0.48 gram (45%) embodiment 45 and the compound of 0.50 gram (45%) embodiment 46.Embodiment 45:( 1H-NMR, 300MHz, CDCl 3) 1.3 (t, 3H), 2.38 (s, 3H), 2.44-2.55 (m, 2H), 2.65 (s, 3H), 2.9-3.02 (m, 1H), 3.08-3.23 (m, 3H), 4.28-4.4 (m, 2H), 6.85-6.92 (m, 1H), 6.95-7.18 (m, 5H), 7.25-7.34 (m, 1H), 9.25 (s, 1H), 11.8 (s, 1H) embodiment 46:( 1H-NMR, 300MHz, CDCl 3) 1.28 (t, 3H), 2.35 (s, 3H), 2.45-2.58 (m, 2H), 2.95 (s, 3H), 3.18 (q, 2H), 3.4 (t, 2H), 4.35 (t, 2H), 6.85-6.92 (m, 1H), 6.95-7.15 (m, 5H), 7.22-7.33 (m, 1H), 9.23 (s, 1H), 11.83 (s, 1H)
Embodiment 47
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(3-methylthio group propoxy-) quinoline
The mixture heating up to 55 in toluene ℃ and stir and spend the night with 0.95 gram (2.8 mmole) 3-butyryl-4-chloro-8-(3-methylthio group propoxy-) quinoline and 1.51 gram (11.8 mmole) 2-chloroanilines.Boil off solvent and at methylene dichloride and saturated NaHCO 3Distribute residue between the solution.Use Na 2SO 4Dry organic layer also evaporates it, with chromatogram (SiO 2CH 2Cl 2: purification residue MeOH 95: 5) obtains 0.95 gram (74%) required product.( 1H-NMR,500MHz,CDCl 3)0.95-1.05(t,3H),1.75-1.85(m,2H),2.10(s,3H),2.20-2.30(m,2H),2.70-2.80(m,2H),3.0-3.10(m,2H),4.20-4.30(m,2H),6.80(d,1H),6.95-7.10(m,5H),7.40(d,1H),9.20(s,1H),11.6(s,1H).
Embodiment 48
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(3-methylsulfinyl propoxy-) quinoline
0.31 gram (0.72 mmole) 3-butyryl-4-(2-chloro-phenyl-amino)-8-(3-methylthio group propoxy-) quinoline is dissolved in 10 milliliters of methylene dichloride, add 5 ml waters, add the solution of 5%NaOCl in 10 milliliters of methylene dichloride of 1.5 milliliters (1.09 mmoles) then.In this mixture of stirring at room 4 hours.Separate organic phase and evaporate it.Use methylene dichloride: methyl alcohol is made the elutriant chromatogram and is purified at 95: 5, obtains the title compound of 0.104 gram (32%).( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,3H),2.45-2.55(m,2H),2.65(s,3H),2.90-3.0(m,1H),3.05-3.15(m,2H),3.15-3.20(m,1H),4.30-4.40(m,2H),6.85(d,1H),7.0-7.15(m,5H),7.45(d,1H),9.25(s,1H),11.60(s,1H)
Embodiment 49
Preparation 3-butyryl-4-(2-chloro-phenyl-amino)-8-(3-methylsulfonyl propoxy-) quinoline
With 0.31 gram (0.72 mmole) 3-butyryl-4-(2-chloro-phenyl-amino)-8-(3-methylthio group propoxy-) quinoline solution and 0.27 gram (3.2 mmole) NaHCO in 5 milliliters of methylene dichloride 3The mixture that solution in 5 ml waters forms is cooled to 4 ℃.Drip the solution of m-CPBA in 10 milliliters of methylene dichloride of 0.4 gram (1.63 mmole) 70%.After 1 hour, use saturated NaHCO 4 ℃ of stirrings 3The solution washing organic layer.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: MeOH 95: 5) purify, obtain the required product of 69 milligrams (21%).( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,2H),2.50-2.55(m,2H),3.00(s,3H),3.05-3.10(m,2H),3.40-3.45(m,2H),4.35-4.40(m,2H),6.80-6.85(m,1H),7.00-7.20(m,5H),7.45-7.50(m,1H),9.25(s,1H),11.60(s,1H)
Embodiment 50
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(3-methylthio group propoxy-) quinoline
0.95 gram (2.97 mmole) 3-butyryl-4-chloro-8-(3-methylthio group propoxy-) quinoline made a din and the mixtures of 1.27 gram (11.8 mmole) 2-aminotoluenes are heated to 55 ℃ and stir and spend the night in toluene.Steam solvent and at methylene dichloride and saturated NaHCO 3Distribute residue between the solution.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: purification residue MeOH 95: 5) obtains 0.98 gram (80.9%) required product.( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.75-1.80(m,2H),2.10(s,3H),2.25-2.30(m,2H),2.35(s,3H),2.75-2.80(m,2H),3.05-3.10(m,2H),4.25-4.30(m,2H),7.85-7.90(d,1H),6.95-7.15(m,5H),7.25(d,1H),9.20(s,1H),11.75(s,1H)
Embodiment 51
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(3-methylsulfinyl propoxy-) quinoline
0.33 gram (0.8 mmole) 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(3-methylthio group propoxy-) quinoline is dissolved in 15 milliliters of methylene dichloride, add 5 ml waters, add the solution of NaOCl in 1.0 milliliters of methylene dichloride of 1.5 milliliters of (1.09 mmoles) 5% then.In room temperature this mixture was stirred 4 hours.Isolate organic phase and evaporate it.Use methylene dichloride: methyl alcohol is made the elutriant chromatogram and is purified at 95: 5, obtains 0.18 gram (53%) title compound.( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.75-1.85(m,2H),2.30(s,3H),2.40-2.50(m,2H),2.60(s,3H),2.90-3.15(m,4H),4.25-4.40(m,2H),6.85-6.90(m,1H),6.95-7.15(m,5H),7.25-7.30(m,1H),9.20(s,1H),11.90(s,1H)
Embodiment 52
Preparation 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(3-methylsulfonyl propoxy-) quinoline
With 0.33 gram (0.81 mmole) 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(3-methylthio group propoxy-) quinoline solution and 0.27 gram (3.2 mmole) NaHCO in 5 milliliters of methylene dichloride 3The mixture of the solution composition in 5 ml waters is cooled to 4 ℃.Drip the solution of m-CPBA in 10 milliliters of methylene dichloride of 0.4 gram (1.63 mmole) 70%.After stirring 1 hour under 4 ℃, use saturated NaHCO 3The solution washing organic layer.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: MeOH 95: 5) purify, obtain 99 milligrams of (28%) required products.( 1H-NMR,500MHz,CDCl 3):1.05(t,3H),1.80-1.90(m,2H),2.35(s,3H),2.50-2.55(m,2H),3.00(s,3H),3.10-3.15(m,2H),3.35-3.45(m,2H),4.35-4.40(m,2H),6.85-6.90(m,1H),6.95-7.15(m,5H),7.25-7330(m,1H),9.20(s,1H),11.85(s,1H)
Embodiment 53
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(3-methylthio group propoxy-) quinoline
The mixture of 0.95 gram (2.97 mmole) 3-butyryl-4-chloro-8-(3-methylthio group propoxy-) quinoline and 1.46 gram (11.8 mmole) 2-anisidines is heated to 55 ℃ in toluene, and stirs and spend the night.Steam solvent and at methylene dichloride and saturated NaHCO 3Distribute residue between the solution.Use Na 2SO 4Dry organic layer also evaporates it, with chromatogram (SiO 2CH 2Cl 2: purification residue MeOH 95: 5) obtains 0.90 gram (71%) required product.( 1H-NMR,300MHz,CDCl 3):1.05(t,3H),1.75-1.90(m,2H),2.10(s,3H),2.25-2.35(m,2H),2.75-2.80(m,2H),3.05-3.10(m,2H),3.80(s,3H),4.25-4.35(m,2H),6.75-6.85(m,1H),6.90-7.20(m,5H),7.25-7.30(m,1H),9.20(s,1H),11.65(s,1H)
Embodiment 54
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(3-methylsulfinyl propoxy-) quinoline
0.30 gram (0.70 mmole) 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(3-methylthio group propoxy-) quinoline is dissolved in 10 milliliters of methylene dichloride, add 5 ml waters, add the solution of NaOCl in 10 milliliters of methylene dichloride of 1.5 milliliters of (1.09 mmoles) 5% then.In this mixture of stirring at room 4 hours.Isolate organic phase and evaporate it.Use methylene dichloride: methyl alcohol is made the elutriant chromatogram and is purified at 95: 5, obtains 14 milligrams of (4.6%) title compounds.( 1H-NMR,500MHz,CDCl 3)1.0(t,3H),1.75-1.85(m,2H),2.45-2.55(m,2H),2.63(s,3H),2.95(m,1H),3.05-3.10(m,2H),3.15(m,1H),3.8(s,3H),4.30(m,1H),4.40(m,1H),6.80-7.20(m,6H),7.30(m,1H),9.20(s,1H),11.6(s,1H)
Embodiment 55
Preparation 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(3-methylsulfonyl propoxy-) quinoline
With 0.30 gram (0.71 mmole) 3-butyryl-4-(2-p-methoxy-phenyl amino)-8-(3-methylthio group propoxy-) quinoline solution and 0.27 gram (3.2 mmole) NaHCO in 5 milliliters of methylene dichloride 3The mixture of the solution composition in 5 ml waters is cooled to 4 ℃.Drip the solution of m-CPBA in 10 milliliters of methylene dichloride of 0.4 gram (1.63 mmole) 70%.4 ℃ stir 1 hour after, with saturated NaHCO 3This organic layer of solution washing.Use Na 2SO 4Dry organic layer also evaporates it.Chromatogram (SiO 2CH 2Cl 2: MeOH 95: 5) purify, obtain the required product of 41 milligrams (13%).( 1H-NMR,500MHz,CDCl 3)1.05(t,3H),1.80-1.90(m,2H),2.50-2.55(m,2H),3.00(s,3H),3.05-3.10(m,2H),3.40-3.45(m,2H),3.80(s,3H),4.35-4.40(m,2H),6.80-7.15(m,6H),7.30-7.35(m,1H),9.20(s,1H),11.60(s,1H)
Embodiment 56
Analyse out 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline racemic modification
3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline and 3.45 gram (0.023 mmole) D-(-)-tartaric mixture reflux in 180 ml methanol with 9.3 grams (0.023 mmole).Allow solution be chilled to the room temperature restir 60 hours.Filter out precipitation, wash, obtain 6.1 gram tartrates (filtrate is used among the embodiment 57) with the first ferment of 20 milliliters of total quantitys.Repeat the tartrate that 3 recrystallizations obtain 3.05 grams, 1.30 grams and last 1.05 gram embodiment 57 with methyl alcohol.Use NaHCO 3Methylene dichloride and water saturation solution this salt that neutralizes, use Na 2SO 4Dry organic layer steams solvent, with the isopropyl ether development, obtains the pure enantiomorph of 0.7 gram.
Embodiment 57
Analyse out 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline
The evaporation filtrate that crystallization for the first time obtains in embodiment 56.Be used in the saturated NaHCO in ethylene dichloride and the water 3Solution this salt that neutralizes.Use Na 2SO 4Dry this organic layer, and boil off solvent.Solid residue and 1.68 gram (0.011 mole) L-(+)-tartrate of 4.6 grams (0.011 mole) are dissolved in 110 milliliters of warm methyl alcohol.This solution is cooled to room temperature and stirred 72 hours.Leach precipitation and, obtain 1.5 and restrain tartrates with the methanol wash of 11 milliliters of total quantitys.Use recrystallizing methanol, obtain the tartrate of 1.05 gram embodiment 57.Be used in the saturated NaHCO in methylene dichloride and the water 3Solution this salt that neutralizes.Use Na 2SO 4Dry organic layer, and boil off solvent.Obtain the pure enantiomorph of 0.7 gram with the isopropyl ether development.
On the Chiralpak of 250 * 4.6mm i.d. AD (Daciel, Japan) pillar, use following parameter enantiomer separation:
Normal hexane: 2-propyl alcohol: acetonitrile: diethylamine (82: 18: 2: 0.1);
Temperature: 35 ℃; Flow velocity: 0.8 ml/min.
The enantiomorph of embodiment 56: retention time 14.5 minutes
The enantiomorph of embodiment 57: retention time 18.4 minutes
Table 1 embodiments of the invention compound summary sheet
Embodiment R 1 R 2 R 3 R 4 m n
1 CH 2CH 2CH 3 CH 3 CH 3 H 2 0
2 CH 2CH 2CH 3 CH 3 CH 3 H 2 1
3 CH 2CH 2CH 3 CH 3 CH 3 H 2 2
4 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 0
5 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 1
6 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 2
7 CH 2CH 3 CH 3 CH 3 H 2 0
8 CH 2CH 3 CH 3 CH 3 H 2 1
9 CH 2CH 3 CH 3 CH 3 H 2 2
10 CH 2CH 3 CH 2CH 3 CH 3 H 2 0
11 CH 2CH 3 CH 2CH 3 CH 3 H 2 1
12 CH 2CH 3 CH 2CH 3 CH 3 H 2 2
13 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 0
14 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 1
15 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 2
16 CH 2CH 3 CH(CH 3) 2 CH 3 H 2 0
17 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 0
18 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 1
19 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 2
20 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 0
21 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 1
22 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 2
23 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 0
Embodiment R 1 R 2 R 3 R 4 m n
24 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 1
25 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 2
26 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 0
27 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 1
28 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 2
29 CH 2CH 2CH 3 Cl CH 3 H 2 0
30 CH 2CH 2CH 3 Cl CH 3 H 2 1
31 CH 2CH 2CH 3 Cl CH 3 H 2 2
32 CH 2CH 2CH 3 OCH 3 CH 3 H 2 0
33 CH 2CH 2CH 3 OCH 3 CH 3 H 2 1
34 CH 2CH 2CH 3 OCH 3 CH 3 H 2 2
35 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 0
36 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 1
37 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 2
38 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 0
39 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 1
40 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 2
41 CH 2CH 2CH 3 CH 3 CH 3 6-Cl 2 0
42 CH 2CH 2CH 3 CH 3 CH 3 6-Cl 2 1
43 CH 2CH 2CH 3 CH 3 CH 3 6-Cl 2 2
44 CH 2CH 3 CH 3 CH 3 H 3 0
45 CH 2CH 3 CH 3 CH 3 H 3 1
46 CH 2CH 3 CH 3 CH 3 H 3 2
47 CH 2CH 2CH 3 Cl CH 3 H 3 0
48 CH 2CH 2CH 3 Cl CH 3 H 3 1
Embodiment R 1 R 2 R 3 R 4 m n
49 CH 2CH 2CH 3 Cl CH 3 H 3 2
50 CH 2CH 2CH 3 CH 3 CH 3 H 3 0
51 CH 2CH 2CH 3 CH 3 CH 3 H 3 1
52 CH 2CH 2CH 3 CH 3 CH 3 H 3 2
53 CH 2CH 2CH 3 OCH 3 CH 3 H 3 0
54 CH 2CH 2CH 3 OCH 3 CH 3 H 3 1
55 CH 2CH 2CH 3 OCH 3 CH 3 H 3 2
2. intermediate preparation
Below the intermediate that uses according to The compounds of this invention in preparation of each embodiment explanation:
The embodiment I
Preparation 2-(2-methylthio group ethoxy base) oil of mirbane
18.0 gram (0.16 mole) 2-methylthio group monochloroethane, 20.8 gram (0.15 mole) o-NPs and 24.7 gram (0.18 mole) salt of wormwood were refluxed in acetonitrile 24 hours.Filter reaction mixture also steams solvent.Residue is dissolved in the methylene dichloride, and washes with water once, and then use saturated Na 2CO 3Solution is washed 2 times.Use Na 2SO 4Dry this organic layer steams solvent, obtains the title compound of 20.2 gram (63%) oily residues.( 1H-NMR,300MHz,CDCl 3),2.21(s,3H),2.90(t,2H),4.27(t,2H),7.04(m,2H),7.50(m,1H),7.79(m,1H).
The embodiment II
Preparation 2-(2-methylthio group ethoxy base) aniline
The 57.9 gram solution of (0.26 mole) two hydration tin chlorides in 90 milliliters of ethanol are added in 18.1 gram (0.085 mole) 2-(2-methylthio group ethoxy base) oil of mirbane, 72.4 milliliters of concentrated hydrochloric acids and the 36 milliliters of alcoholic acid mixtures.In room temperature reaction mixture was stirred 24 hours.The NaOH that in reaction mixture, adds 270 milliliters of 6M.With dichloromethane extraction (3 * 400 milliliters), using Na 2SO 4Dry organic layer and steam solvent after, obtain 14.8 gram (95%) title compounds.( 1H-NMR,300MHz,CDCl 3),2.28(s,3H),2.90(t,2H),4.18(t,2H),4.83(b,2H),6.66-6.83(m,4H).
The embodiment III
Preparation 2-butyryl-3-(2-(2-methylthio group ethoxy base) phenyl amino) ethyl propenoate
The mixture heating up to 120 of 1.6 gram (8.7 mmole) 2-(2-methylthio group ethoxy base) aniline, 1.38 gram (8.7 mmole) butyryl vinyl acetic monomers and 1.30 gram (8.8 mmole) triethyl orthoformates ℃ is reached 1 hour, steam ethanol.Reaction mixture is cooled to room temperature.With the development of first ferment, obtain 1.08 gram (35%) solid required compounds.( 1H-NMR,300MHz,CDCl 3)0.96(t,3H),1.33(t,3H),1.68(m,3H),2.22(s,3H),2.92(t,2H),3.00(t,2H),4.25(m,4H),6.9-7.3(m.4H),8.5(d,1H),12.81(d,1H).
The embodiment IV
Preparation 3-butyryl-8-(2-methylthio group ethoxy base)-4 (1H)-quinolones
1.07 gram (3.04 mmole) 2-butyryl-4-(2-(2-methylthio group ethoxy base) phenyl amino) ethyl propenoates are added in the diphenyl ether of backflow.This mixture refluxed 50 minutes, and reaction mixture is cooled to room temperature.Add 70 milliliters of sherwood oils, filtered out precipitation later in 90 minutes, obtain the title compound of 0.8 gram (85%) at further this mixture that stirs.( 1H-NMR,500MHz,CDCl 3),1.02(t,3H),1.75(m,2H),2..22(s,3H),3.00(t,2H),3.25(t,2H),4.36(t,2H),7.15(d,1H),7.35(m,1H),8.06(d,1H),8.58(s,1H),9.40(b,1H).
The embodiment V
Preparation 3-butyryl-4-chloro-8-(2-methylthio group ethoxy base)-quinolone
In room temperature 0.8 gram (2.8 mmole) 3-butyryl-8-(2-methylthio group ethoxy base)-4 (1H)-quinolones and 10 milliliters of phosphorus oxychlorides were stirred 1 hour.Evaporate phosphorus oxychloride.Between water and methylene dichloride, distribute residue.Use NaHCO 3PH is transferred to 8.Use Na 2SO 4Dry organic layer steams solvent, obtains 0.57 gram (68%) required compound.( 1H-NMR,300MHz,CDCl 3),0.97(t,3H),1.86(m,2H),2.22(s,3H),3.00(t,2H),3.05(t,2H),4.38(t,2H),7.16(d,1H),7.57(m,1H),287(d,1H),8.84(s,1H).
The embodiment VI
Preparation 3-propionyl-4-chloro-8-(2-methylthio group ethoxy base) quinoline
Method according to the embodiment V prepares title compound, productive rate 0.6 gram (75%).( 1H-NMR,300MHz,CDCl 3)1.26(t,3H),2..26(s,3H),3.01-3.07(m,4H),4.39(t,2H),7.15(d,1H),7.55(m,1H),7.85(d,1H),8.84(s,1H).
The embodiment VII
Preparation 3-propionyl-4-chloro-8-(2-rosickyite base oxethyl) quinoline is made a din
According to the synthetic 3-propionyl of embodiment V-4-chloro-8-(2-rosickyite base oxethyl) quinoline, productive rate 2.5 grams (88%).( 1H-NMR,300MHz,CDCl 3)0.97(t,3H),1.23(t,3H),1.62(m,2H),261(t,2H),3.00-3.09(m,4H),4.36(t,2H),7.15(d,1H),7.57(t,1H),7.87(d,1H),8.85(s,1H).
The embodiment VIII
Preparation 3-propionyl-4-chloro-8-(2-rosickyite base propoxy-) quinoline
According to the synthetic 3-propionyl of embodiment V-4-chloro-8-(2-rosickyite base propoxy-) quinoline, productive rate 5.5 grams (87%).( 1H-NMR,300MHz,CDCl 3)0.90(t,3H),1.20(t,3H),1.54(m,2H),2.22(m,2H),2.44(t,2H),2.72(t,2H),3.00(q,2H),4.30(t,2H),7.14(d,1H),7.53(t,1H),7.81(d,1H),8.83(s,1H).
The embodiment IX
Preparation 3-butyryl-4-chloro-8-(3-methylthio group propoxy-) quinoline
According to the method synthesising title compound of embodiment V, productive rate 2.9 gram (91%) (hydrochlorides).( 1H-NMR,500MHz,CDCl 3)1.02(t,3H),1.8(m,2H),2.30(s,3H),2.40(m,2H),2.90(t,2H),3.10(t,2H),4.50(t,2H),7.52(d,1H),7.90-7.95(m,1H),8.30-8.50(m,1H),9.48(s,1H).
The embodiment X
Preparation 3-propionyl-4-chloro-8-(3-methylthio group propoxy-) quinoline
According to the method synthesising title compound of embodiment V, productive rate 3.95 grams (96%).( 1H-NMR,300MHz,CDCl 3)1.28(t,3H),2.1(s,3H),2.3(q,2H),2.8(t,2H),3.08(q,2H),4.38(t,2H),7.23(d,1H),7.6(t,1H),7.9(d,1H),8.9(s,1H).
3. prepare the medicine prescription
Contain the medicine prescription of The compounds of this invention with following each embodiment explanation as actives
Prescription A. syrup
The syrup that contains actives 1% (weight/volume) by following each composition preparation:
Compound 1.0 grams according to embodiment 2
Sucrose, powder 30.0 grams
Asccharin 0.6 gram
Glycerine 5.0 grams
Flavouring agent 0.05 gram
Ethanol 96% 5.0 grams
Distilled water makes final volume reach 100 milliliters in right amount
Sucrose and asccharin are dissolved in the 60 gram warm water.After the cooling, acid salt is dissolved in this sugar soln and the glycerine, adds the solution of flavouring agent in ethanol.This mixture of dilute with water makes final volume reach 100 milliliters.
Given actives above can replacing with the acceptable acid salt of other medicines.
Prescription B. tablet
The tablet that contains 50 milligrams of activess by following each composition preparation:
I is according to compound 500 grams of embodiment 2
Lactose 700 grams
Methylcellulose gum 6 grams
Cross-linking polyethylene Mierocrystalline cellulose 50 grams
Magnesium Stearate 15 grams
Yellow soda ash 6 grams
Distilled water is an amount of
II Vltra tears 36 grams
Polyoxyethylene glycol 9 grams
Painted titanium dioxide 4 grams
Pure water 313 grams
I. Powdered compound according to embodiment 2 mixes with lactose, and with methylcellulose gum and aqueous sodium carbonate granulation.Wet granular is sieved and drying in baking oven.After the drying this particle is mixed with Polyvinylpyrolidone (PVP) and Magnesium Stearate, this dry mixture is pressed into label (10,000), every contains 50 milligrams of activess, and compressing tablet uses 7 mm dias to press the tabletting machine in hole.
II. preparation Vltra tears and the solution of polyoxyethylene glycol in pure water.After titanium dioxide is disperseed, with this solution at Accela Cota Be coated on the tablet I in (Manestry coating apparatus company) coating machine.Obtain final weight and be 130 milligrams tablet.
Prescription C: intravenously administrable solution
Intravenously with the outer prescription of intestines contain 4 milligrams of activess/liter, by following various one-tenth assignment systems.
Compound 4 grams according to embodiment 2
Injection poly(oxyethylene glycol) 400 400 grams
Sodium phosphate dibasic is an amount of
It is 1000 milliliters that aqua sterilisa is added to final volume
To be dissolved in the poly(oxyethylene glycol) 400 according to the compound of embodiment 2, and add 550 ml waters.Add Na 2HPO 3The aqueous solution is transferred to pH7.4 with the pH value of solution, adds water again and makes final volume reach 1000 milliliters.Filtering this solution and being sub-packed in immediately in 10 milliliters of sterilization ampoules and with ampoule by 0.22 micron filter seals.
4. biological test
A. according to people such as Berglindh (1976) at Acta Physiol.Scand.97, the method described in the 401-414 carries out in vitro measuring gastric acid secretion is inhibiting with separating the rabbit gastric gland.IC according to the compound of embodiment 1～12 50Value is in the scope of 0.5～0.6 μ M.IC according to the compound of embodiment 13～57 50Value is in 0.75～14 μ M scope.
B. measure as follows and do not anaesthetize female mouse in vivo to the restraining effect of gastric acid secretion.
Use the female mouse of Sprague-Dauly kind.Its stomach (chamber) and duodenal cap device the sleeve pipe fistula, be used for collecting the secretion and the drop-test material of stomach respectively.After operation, began test again through 14 day decubation.
Before the secretion test, animal fasting in 20 hours time, but can't help water.Overlap effective 37 ℃ tap water repeated gastric lavage by stomach, again from 6 milliliters of woods lattice of subcutaneous injection Glucose Liquid.In 3 hours, by inject pentagastrin and Samoryl (subcutaneous injection, speed be 1.2 milliliters/time, injection rate is respectively 20 and 110 nmole/kilograms hour) gastric acid secretion.During this period, gastric secretions was collected at the interval in per 30 minutes.By feeding substances or carrier in intravenously or the duodenum, administration when beginning to stimulate back 60 minutes, 1.2 milliliters/hour of dosages.It is 7 that the gastric juice sample is titrated to the pH value with the NaOH of 0.1 mol.Calculate out the acid amount by titration capacity and concentration product.
On average reply further based on the group of 4～5 mouse and to calculate.Sour generation behind administration or carrier in for some time is expressed as part and replys, and the preceding 30 minutes sour secretory volume of not offeing medicine is 1.0.The part that is excited by test compounds and carrier is replied and is calculated inhibition percentage ratio.Calculate ED in log10 dose～response curve mapping interpolation 50, perhaps similar slope of full dosage one response curve hypothesis is estimated ED by the single dose experiment 50
The ED of the compound 1～12 in the table I 50Value is between 1.0～12 micromole/kilograms.This result is based on behind administration/carrier that the secretion of hydrochloric acid in gastric juice obtains in second hour.

Claims (10)

1. the acceptable salt of the medicine of the compound of formula I or described compound,
Figure C9419241000021
R wherein 1Be (a) C 1～C 6Alkyl, (b) C 3～C 6Cycloalkyl, perhaps (c) C 3～C 6Cycloalkyl C 1～C 6Alkyl; R 2Be (a) H, (b) C 1～C 6Alkyl, (c) C 1～C 6Alkoxyl group, perhaps (d) halogen; R 3Be C 1～C 6Alkyl;
R 4Be
(a)H
(b) C 1～C 4Alkyl,
(c) halogen, perhaps
(d)OH；
M is integer 2 or 3; And
N is an integer 0,1 or 2.
2. according to the compound of claim 1 or the acceptable salt of medicine of described compound, wherein
R 1Be CH 3, CH 2CH 3, CH 2CH 2CH 3, CH (CH 3) 2, cyclopropyl or cyclopropyl methyl;
R 2Be CH 3, CH 2CH 3, CH 2CH 2CH 3, CH (CH 3) 2, CH (CH 3) CH 2CH 3, OCH 3, OCH 2CH 3Or halogen;
R 3Be CH 3, CH 2CH 3, CH (CH 3) 2Or CH 2CH 2CH 3And
R 4Be H, CH 3, CH 2CH 3, halogen or OH.
3. according to the compound of claim 2 or the acceptable salt of medicine of described compound, wherein
R 1Be CH 2CH 3Or CH 2CH 2CH 3
R 2Be CH 3, CH 2CH 3, CH (CH 3) 2, OCH 3Or Cl;
R 3Be CH 3, CH 2CH 3Or CH 2CH 2CH 3And
R 4Be H, CH 3, F, Cl or OH.
4. according to the compound of claim 3 or the acceptable salt of medicine of described compound, they are one of listed all cpds of following table, Embodiment R 1 R 2 R 3 R 4 m n 1 CH 2CH 2CH 3 CH 3 CH 3 H 2 0 2 CH 2CH 2CH 3 CH 3 CH 3 H 2 1 3 CH 2CH 2CH 3 CH 3 CH 3 H 2 2 4 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 0 5 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 1 6 CH 2CH 2CH 3 CH(CH 3) 2 CH 3 H 2 2 7 CH 2CH 3 CH 3 CH 3 H 2 0 8 CH 2CH 3 CH 3 CH 3 H 2 1 9 CH 2CH 3 CH 3 CH 3 H 2 2 10 CH 2CH 3 CH 2CH 3 CH 3 H 2 0 11 CH 2CH 3 CH 2CH 3 CH 3 H 2 1 12 CH 2CH 3 CH 2CH 3 CH 3 H 2 2 13 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 0 14 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 1 15 CH 2CH 2CH 3 CH 3 CH 3 4-F 2 2 16 CH 2CH 3 CH(CH 3) 2 CH 3 H 2 0 17 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 0 18 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 1 19 CH 2CH 2CH 3 CH 2CH 3 CH 3 H 2 2 20 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 0 21 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 1
Embodiment R 1 R 2 R 3 R 4 m n 22 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 2 2 23 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 0 24 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 1 25 CH 2CH 3 CH 3 CH 2CH 2CH 3 H 3 2 26 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 0 27 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 1 28 CH 2CH 2CH 3 CH 3 CH 3 4-OH 2 2 29 CH 2CH 2CH 3 Cl CH 3 H 2 0 30 CH 2CH 2CH 3 Cl CH 3 H 2 1 31 CH 2CH 2CH 3 Cl CH 3 H 2 2 32 CH 2CH 2CH 3 OCH 3 CH 3 H 2 0 33 CH 2CH 2CH 3 OCH 3 CH 3 H 2 1 34 CH 2CH 2CH 3 OCH 3 CH 3 H 2 2 35 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 0 36 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 1 37 CH 2CH 2CH 3 CH 3 CH 3 4-CH 3 2 2 38 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 0 39 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 1 40 CH 2CH 2CH 3 CH 3 CH 3 6-CH 3 2 2 41 CH 2CH 2CH 3 CH 3 CH 3 6-Cl 2 0 42 CH 2CH 2CH 3 CH 3 CH 3 6-Cl 2 1
Embodiment R 1 R 2 R 3 R 4 m n 43 CH 2CH 2CH 3 CH 3 CH 3 6-C 2 2 44 CH 2CH 3 CH 3 CH 3 H 3 0 45 CH 2CH 3 CH 3 CH 3 H 3 1 46 CH 2CH 3 CH 3 CH 3 H 3 2 47 CH 2CH 2CH 3 Cl CH 3 H 3 0 48 CH 2CH 2CH 3 Cl CH 3 H 3 1 49 CH 2CH 2CH 3 Cl CH 3 H 3 2 50 CH 2CH 2CH 3 CH 3 CH 3 H 3 0 51 CH 2CH 2CH 3 CH 3 CH 3 H 3 1 52 CH 2CH 2CH 3 CH 3 CH 3 H 3 2 53 CH 2CH 2CH 3 OCH 3 CH 3 H 3 0 54 CH 2CH 2CH 3 OCH 3 CH 3 H 3 1 55 CH 2CH 2CH 3 OCH 3 CH 3 H 3 2
5. this compound of compound according to claim 1 is 3-butyryl-4-(2-aminomethyl phenyl amino)-8-(2-methylsulfinyl oxyethyl group) quinoline or its drug salts.
6. prepare the method for the compound of claim 1, it comprises:
(a) compound of the compound of general formula II and general formula III reaction, R wherein 2And R 2Such as claim 1 definition,
Figure C9419241000071
R wherein 1, R 3, m and n such as claim 1 definition, X is a leavings group that is selected from halogen, tosyloxy or mesyloxy; Perhaps
(b) by R in the oxidation-type 1, R 2, R 3, R 4With m such as claim 1 definition, and R in the formula I compound formula of n=0 1, R 2, R 3, R 4With m such as claim 1 definition, and the formula I compound of n=1 or 2.
7. according to the method for claim 6, wherein said oxidation step is implemented by the following method:
(ⅰ) use oxygenant, allow oxidizing reaction in the solvent that is selected from halohydrocarbon, alcohols, ethers or ketone, carry out; Perhaps
(ⅱ) use oxydase to carry out oxydasis; Perhaps
(ⅲ) carry out microbiological oxidation with suitable microorganism.
8. contain the pharmaceutical composition that each desired compound is an activeconstituents in the claim 1 to 5.
9. the application of each desired compound aspect preparation gastric acid inhibitory secretion medicine in the claim 1 to 5.
As each desired compound in the claim 1 to 5 in the application aspect the preparation treatment gastrointestinal inflammation medicine.
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CN1125438A (en) 1996-06-26
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